The present invention relates to certain pyrazolo-triazolo-pyrimidine, triazolo-triazolo-pyrimidine and imidazolo-triazolo-pyrimidine derivatives and their use in the practice of medicine as modulators of adenosine A3 receptors.
Three major classes of adenosine receptors, classified as A1, A2, and A3, have been characterized pharmacologically. A1 receptors are coupled to the inhibition of adenylate cyclase through Gi proteins and have also been shown to couple to other second messenger systems, including inhibition or stimulation of phosphoinositol turnover and activation of ion channels. A2A receptors are further divided into two subtypes, A2A and A2B, at which adenosine agonists activate adenylate cyclase with high and low affinity, respectively. The A3 receptor sequence was first identified in a rat testes cDNA library, and this sequence, later cloned by homology to other G-protein coupled receptors from a rat brain cDNA library, was shown to correspond to a novel, functional adenosine receptor.
The discovery of the A3 receptor has opened new therapeutic vistas in the purine field. In particular, the A3 receptor mediates processes of inflammation, hypotension, and mast cell degranulation. This receptor apparently also has a role in the central nervous system. The A3 selective agonist IB-MECA induces behavioral depression and upon chronic administration protects against cerebral ischemia. A3 selective agonists at high concentrations were also found to induce apoptosis in HL-60 human leukemia cells. These and other findings have made the A3 receptor a promising therapeutic target. Selective antagonists for the A3 receptor are sought as potential anti inflammatory or possibly antiischemic agents in the brain. Recently, A3 antagonists have been under development as antiasthmatic, antidepressant, antiarrhythmic, renal protective, antiparkinson and cognitive enhancing drugs.
It is therefore an object of the present invention to provide compounds and methods of preparation and use thereof, which are agonists, partial agonists, and/or antagonists of the adenosine A3 receptor.
Compounds useful as potent, yet selective modulators of the adenosine A3 receptor, with activity as antagonists of this receptor, and methods of preparation and use thereof, are disclosed.
The compounds have the following general formula: 
wherein:
A is imidazole, pyrazole, or triazole;
R is xe2x80x94C(X)R1, xe2x80x94C(X)xe2x80x94N(R1)2, xe2x80x94C(X)OR1, xe2x80x94C(X)SR1, xe2x80x94SOnR1, xe2x80x94SOnOR1, xe2x80x94SOnSR1 or SOnxe2x80x94N(R1)2;
R1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms such as N, O, S;
R2 is hydrogen, alkyl, substituted alkyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
R3 is furan, pyrrole, thiophene, benzofuran, benzopyrrole, benzothiophene, optionally substituted with one or more substituents as described herein for substituted heteroaryl rings;
X is O, S, or NR1;
n is 1 or 2; and
and pharmaceutically acceptable salts thereof.
Preferably, R1 is hydrogen; C1 to C8 alkyl; C3 to C7 alkenyl, C3 to C7 alkynyl; C3 to C7 cycloalkyl; C1 to C5 alkyl substituted with one or more halogen atoms, hydroxy groups, C1 to C4 alkoxy, C3 to C7 cycloalkyl or groups of formula xe2x80x94NR12, xe2x80x94CO NR12; aryl, substituted aryl wherein the substitution is selected from the group consisting of C1 to C4 alkoxy, C1 to C4 alkyl, nitro, amino, cyano, C1 to C4 haloalkyl, C1 to C4 haloalkoxy, carboxy, carboxyamido; C7 to C10 aralkyl in which the aryl moiety can be substituted with one or more of the substituents indicated above for the aryl group; a group of formula xe2x80x94(CH2)m-Het, wherein Het is a 5-6 membered aromatic or non aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of N, O, and S and m is an integer from 1 to 5;
Preferred C1 to C8 alkyl groups are methyl, butyl and isopentyl. Examples of C3 to C7 cycloalkyl groups include cyclopropyl, cyclopentyl, and cyclohexyl. Examples of C1 to C5 alkyl groups substituted with C3 to C7 cycloalkyl groups include cyclohexylmethyl, cyclopentylmethyl, and 2-cyclopentylethyl. Examples of substituted C1 to C5 alkyl groups include 2-hydroxyethyl, 2-methoxyethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 3-aminopropyl, 2-(4methyl-1-piperazine)ethyl, 2-(4-morpholinyl)ethyl, 2-aminocarbonylethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl. Aryl is preferably phenyl, optionally substituted with Cl, F, methoxy, nitro, cyano, methyl, trifluoromethyl, difluoromethoxy groups. Examples of 5 to 6 membered ring heterocyclic groups containing N, O and/or S include piperazinyl, morpholinyl, thiazolyl, pyrazolyl, pyridyl, furyl, thienyl, pyrrolyl, triazolyl, tetrazolyl. Examples of C7 to C10 aralkyl groups comprise benzyl or phenethyl optionally substituted by one or more substituents selected from Cl, F, methoxy, nitro, cyano, methyl, trifluoromethyl, and difluoromethoxy. Preferably, R is hydrogen, C1 to C8 alkyl, aryl or C7 to C10 aralkyl, optionally substituted, preferably with halogen atoms.
Particularly preferred compounds are those in which R is a phenethyl group in which the phenyl ring is substituted with one or more substituents selected from the group consisting of chlorine, fluorine atoms, methoxy, nitro, cyano, methyl, trifluoromethyl, and difluoromethoxy groups.
The possible meanings of A can be represented by the following structural formulae: 
The compounds can be used in a method for modulating adenosine A3 receptors in a mammal, including a human. The methods involve administering an effective amount of a compound of formula I sufficient to modulate adenosine A3 receptors in the mammal. Uses for the compounds include:
treating hypertension;
treating inflammatory disorders such as rheumatoid arthritis and psoriasis;
treating allergic disorders such as hay fever and allergic rhinitis;
mast cell degranulation;
antitumor agents;
treating cardiac hypoxia; and
protection against cerebral ischemia;
diagnostic uses, for example, to determine the presence of one or more of the above described medical conditions, or in a screening assay to determine the effectiveness of other compounds for binding to the A3 Ado receptor (i.e., through competitive inhibition as determined by various binding assays), as described in Jacobson and Van Rhee, Purinergic approaches to experimental therapy, Jacobson and Jarvis, ed., Wiley, N.Y., 1997, pp. 101-128; Mathot et al., Brit. J. Pharmacol., 116:1957-1964 (1995); van der Wenden et al., J. Med. Chem., 38:4000-4006 (1995); and van Calenbergh, J. Med. Chem., 40:3765-3772 (1997), the contents of which are hereby incorporated by reference.
The compounds can also be used in a method for fully or partially inhibiting adenylate cyclase (A3) in a mammal, including a human. The methods involve administering an effective amount of a compound of formula I sufficient to fully or partially inhibiting adenylate cyclase in the mammal.
The compounds can be used in a pharmaceutical formulation that includes a compound of formula I and one or more excipients. Various chemical intermediates can be used to prepare the compounds.